Authors :
Presenting Author: Benton Purnell, PhD – Rutgers
Brian Rust, BS – Rutgers University; Jayant Bhasin, Undergraduate – The College of New Jersey; Tracy Lu, Undergraduate – Rutgers University; Steven George, Undergraduate – Rutgers University; Kadiatou Bah, BS – Medgar Evers College; Denise Fedele, PhD – Rutgers University; Detlev Boison, PhD – Rutgers University
Rationale:
Respiratory arrest plays an important role in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). Because adenosine influences both seizures and breathing seizure-induced adenosine surging is an interesting candidate mechanism for SUDEP. The objective of this investigation was to examine the role of adenosine in the severity of seizures, the respiratory sequalae of seizures, and seizure-induced death using mouse models. Improving our understanding of adenosinergic contributions to seizure cessation and seizure-induced death may provide insights into how SUDEP can be prevented while avoiding increased seizure severity.Methods:
Our approach was as follows: (1) Demonstrate the safety of therapeutic adenosine augmentation in the maximal electroshock (MES) seizure model, (2) Examine the effects of pharmacological manipulation of adenosine signaling on seizure severity and seizure-induced death following MES, (3) Examine the effect of transgenic reduction of adenosine metabolism on seizure severity and seizure-induced death in the MES and pentylenetetrazol (PTZ) kindling models, and (4) Examine the effect of transgenic reduction of adenosine metabolism on the postictal hypercapnic ventilatory response.
Results:
Pharmacological inhibition of adenosine metabolism decreased the severity of MES seizures but did not cause an increase in seizure-induced death. Pretreatment with A1 selective and nonselective adenosine receptor antagonists prior to MES caused seizures to be more severe and more likely to cause death. Transgenic reduction in adenosine metabolism increased seizure-induced death after MES and in the PTZ kindling model. Despite the increased mortality, transgenic reduction in adenosine metabolism had no effect on seizure severity in the PTZ kindling model and reduced seizure severity in the MES model.
Conclusions:
Our data demonstrates dichotomous effects of adenosine on seizure severity and vulnerability to seizure-induced death. Our seizure severity data highlights the importance of adenosine as an endogenous anticonvulsant. In addition, our mortality data indicates that excessive adenosine signaling can increase the risk of seizure-induced respiratory arrest despite its beneficial effects on seizure severity.
Funding:
NIH NINDS (D.B.: NS065957, NS103740, NS
NS127846), NIH-funded Rutgers INSPIRE IRACDA Postdoctoral Program (BP, #GM093854).